NO317892B1 - Benzisoxazoles and phenones as alpha-2 antagonists, their preparation and pharmaceutical compositions comprising these - Google Patents

Description

The present invention relates to benzisoxazoles and phenones which have central (X2-adrenoceptor antagonistic activity. It further relates to their preparation, compositions comprising them and their use as a medicine.

Central β-adrenoceptor antagonists are known to increase norepinephrine release by blocking presynaptic β-receptors that exert an inhibitory control on the release of the neurotransmitter. By increasing norepinephrine concentrations, <X2 antagonists can be used clinically for the treatment or prophylaxis of depression, cognitive disorders, Parkinson's disease, diabetes mellitus, sexual dysfunction and impotence, raised intraocular pressure, and diseases related to disturbed enterokinesis, because all these conditions is associated with a lack of norepinephrine in the central or peripheral nervous system.

WO98/45297, published October 15, 1998, discloses 1,2,3,4-tetrahydro-benzofuro[3,2-c]pyridine derivatives having central (X2-adrenoceptor antagonistic activity. l-(4-fluorophenyl)-4-(l ,3,4,5-tetrahydro-2t-pyrido[4,3-b]-indol-2-yl)-1-butanone derivatives are described in Kimura et al.

[Arch. Int. Pharmacodyn. Ther. (1971), 190(1), 124-134], Nagai et al. [Chem. Parm. Bull. (1979), 27(8), 1922-1926], Herbert et al. [J. With. Chem. (1980), 23(6), 635-643 & Mol. Pharmacol. (1980), 17(1), 38-42], Wong et al. [Can. Eur. J. Pharmacol. (1981), 73(2-3), 163-173], Ismaiel et al. [With. Chem. Res. (1996), 6(3), 197-211], WO 95/07075, WO 94/10989, WO 94/08040, JP 47,029,395, DE 2,514,084, ZA 6,705,178, US 3,382,250, US 4,001,263, US 4,228, 35,325 and US 4,228.

4-(3, 4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)-1-(4-fluoro-phenyl)-1-butanone derivatives have been brought to light in Aksanova et

eel. [Chem. Farm. Zh. (1975), 9(1), 7-9] as central nervous system blocking agents.

The compounds of the present invention are new and have a specific and selective binding affinity for the various known subtypes of the 012-adrenoreceptors, i.e. the 0.2^-, a2B~ °9 <X2c-aclrenoceptor ■ Compared to the closest known compounds, the present compounds unexpectedly show an improvement in dissociation between binding affinity for the α2A-adrenerosePtoren °9 dopamine D2 receptor which is particularly useful when treating depression.

The present invention relates to the compounds of formula

The W-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: Alk is 1,5-pentanediyl;

n is 1 or 2;

p is 1 and q is 2; or

p is 2 and q is 1;

X is -O-, -S- or NH;

each R<1> is independently hydrogen, halogen, C1-6 alkyl, nitro, hydroxy or C1-4 alkyloxy;

D is a radical with formula

wherein m is 1 or 2;

each r<3> is independently hydrogen, C 1-4 alkyl, C 1-4 alkyloxy or halo.

As used in the preceding definitions, the term halogen is generic for fluorine, chlorine, bromine and iodine. The term C 1-4 alkyl as a group or part of a group defines straight and branched saturated hydrocarbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2 -methylpropyl and the like. The term C 1-6 alkyl is intended to include C 1-4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like.

The addition salts mentioned herein are intended to include the therapeutically active addition salt forms which the compounds of formula (I) are capable of forming with suitable acids, such as, for example, inorganic acids such as hydrohalo acids, e.g. hydrochloric or hydrobromic acid; sulfur-; sal-peter-; phosphoric acid and similar acids; or organic acids such as, for example, acetic, propane, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic , ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and similar acids.

The pharmaceutically acceptable addition salts mentioned above are also intended to include therapeutically active non-toxic bases, in particular, the metal or amine addition salt forms which the compounds of formula (I) are capable of forming. The salts may conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with suitable organic and inorganic bases such as, for example, the ammonium salts, the alkali and alkaline earth metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. benzathine, N-methyl-D-glucamine, hydrabamine salts,

and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, the salt forms can be converted by treatment with a suitable base or acid into the free acid or base form.

The term addition salt as used above also includes the solvates which the compounds of formula (I) are capable of forming and said solvates are intended to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.

The W-oxide forms of the compounds of formula (I) are intended to include those compounds of formula (I) in which one or more nitrogen atoms have been oxidized to the so-called W-oxide.

The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers with the basic molecular structure.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms, even if they are not explicitly indicated in the formula above, are intended to be included within the scope of the present invention.

When used hereinafter, the term compounds of formula (I) is intended to include also the AT oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.

As used hereinafter, when the position of the R' substituent is referred to, the following numbering is used:

An interesting group of compounds are those compounds of formula (I) in which n is 1 and Ri is hydrogen, chlorine, fluorine, methyl, methoxy or nitro, in particular Ri is hydrogen, chlorine or methoxy.

In the case that R<1> is different from hydrogen, then R1 is suitably attached to the tricyclic ring system at the 6- or 7-position.

Yet another interesting group of compounds are those compounds of formula (I) in which D is a radical of formula (a) and R<3> is fluorine, bromine, methoxy, methyl or hydrogen, especially fluorine.

Compounds of formula (I) in which D is a radical of formula (b) are also of particular interest.

The compounds of formula (I) can generally be prepared by W-alkylating an intermediate of formula (II) with an alkylating reagent of formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A -0,196,132 and in EP-A-0,378,255. In particular, the W-alkylation can be carried out in a reaction-inert solvent such as, for example, methyl isobutyl ketone, N,W-dimethylformamide or N,Ztf-dimethylacetamide, in the presence of a base such as, for example, triethylamine, sodium carbonate or sodium bicarbonate, and optionally in the presence of a catalyst such as, for example, potassium iodide.

In intermediate (III) represents a suitable reactive leaving group such as, for example, halo, e.g. chlorine, bromine or iodine; sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.

In this and the following reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methods generally known in the art such as extraction, crystallization, trituration and chromatography.

The compounds of formula (I) can be converted into each other by following known functional group transformation reactions in the art.

The compounds of formula (I) can also be converted to the corresponding W-oxide forms by following known procedures for converting a trivalent nitrogen to its W-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, e.g. sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxyacids such as, for example, benzenecarboperoxoic acid or halo-substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkyl hydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

A number of intermediates and starting materials are commercially available or are known compounds which can be prepared according to known methods in the art.

For example, some of the intermediates of formula (III) and their preparations are described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.

Intermediates of formula (II) in which X is 0 can be prepared analogously to the procedures described in Cattanach C. et al. (J. Chem. Soc (C), 1971, pp. 53-60); Kartashova T. (Khim. Geterotsikl. Soedin., 1979 (9), pp. 1178-1180) and Zakusov. V. et al. (Izobreteniya, 1992 (15), p. 247). Intermediates of formula (II) in which X is S can be prepared analogously to the procedure described in Capps et al. (J. Am. Chem. Soc, 1953, p. 697) or US-3,752,820.

A special synthesis route for the production of intermediates of formula (II) in which p is 1 and q is 2, the intermediates are represented by formula (II-1), is outlined in scheme 1. Step a can be carried out analogously to the procedure described in Tetrahedron (1981 ), 37, pp. 979-982. Benzofuranes resulting from step c have been used as intermediates in US 4,210,655. The further reaction steps are analogous to the reaction procedures described in US 3,752,820.

Alternatively, intermediates of formula (II-1) can be prepared by using the reaction steps outlined in scheme 2.

Step a can be carried out analogously to the procedure described in Heterocycles (1994), 39(1), pp. 371-380. Step b can be carried out analogously to the procedure described in J. Med. Chem.

(1986), 29(9), pp. 1643-1650. Further reaction steps can be carried out analogously to those described in J. Heterocycl. Chem.

(1979), 16, p. 1321.

Intermediates of formula (II) in which p is 2 and q is 1, the intermediates are represented by formula (II-2), can be prepared according to Synth. Comm., 1995, pp. 3883-3900 and by using methods known in the art. A general procedure is outlined in form 3.

Intermediates of formula (II-2) in which X is -0-, the intermediates are represented by formula (II-2-a), can be prepared as described in Syn. Comm. (1995), pp. 3883-3900 and J. Chem. Soc, 1965, pp. 4939-4953 and by using methods known in the art. A general procedure is outlined in scheme 4. Intermediates of formula (II-2) in which X is -S-, the intermediates are represented by formula (II-2-b), can be prepared according to J. Med. Chem., 1992, 35(7), pp. 1176-1182 and by using methods known in the art. A general procedure is outlined in form 5.

Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of the compounds and intermediates can be obtained using known procedures in the art. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. countercurrent distribution, liquid chromatography and similar methods. Enantiomers can be obtained from racemic mixtures by first converting the racemic mixtures with suitable solvents such as, for example, chiral acids, into mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and similar methods; and finally to convert the separated diastereomeric salts or compounds into the corresponding enantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) can also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

The compounds of formula (I), the W-oxides, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, block the presynaptic <X2 receptors on central noradrenergic neurons and thus increase norepinephrine release. Blocking said receptors will suppress or alleviate a number of symptoms associated with a lack of norepinephrine in the central or peripheral nervous system. Therapeutic indications for the use of the present compounds are depression, cognitive disorders, Parkinson's disease, diabetes mellitus, sexual dysfunction and impotence and raised intraocular pressure.

In particular, the present compounds show a greater dissociation between binding affinity for α 2 receptors and that of dopamine receptors, particularly between α 2 A receptors and dopamine D 2 receptors. This higher dissociation reduces the risk of extrapyramidal side effects (EPS) which may arise from dopamine receptor blockade and which should be avoided in the treatment of depression.

Blockade of α 2 receptors in the central nervous system has also been shown to increase the release of serotonin which may add to the therapeutic effect in depression (Maura et al., 1992, Naunyn-Schmiedeberg's Arch. Pharmacol., 345: 410-416).

It has also been shown that blocking OC2 receptors can induce an increase in extracellular DOPAC (3,4-dihydro-phenylacetic acid) which is a metabolite of dopamine and norepinephrine.

In view of the utility of the present compounds in the treatment of diseases associated with a lack of norepinephrine in the central nervous system, in particular depression and Parkinson's disease, the compounds can be used in a method for treating warm-blooded animals suffering from such diseases, in particular depression and Parkinson's disease, the method comprises the systemic administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

The present compounds are also potentially useful in the treatment of Alzheimer's disease and dementia since <X2 antagonists are known to promote the release of acetylcholine (Tellez et al. 1997, J. Neurochem. 68:778-785). In general, it is contemplated that an effective therapeutic daily amount would be from about 0.01 mg/kg to about 4 mg/kg body weight.

The present invention thus also relates to compounds of formula (I) as defined above for use as a medicine. Furthermore, the present invention also relates to the use of a compound of formula (I) for the production of a drug for the treatment of depression or Parkinson's disease.

Ex vivo as well as in vitro receptor signal transduction and receptor binding studies can be used to assess the (X2~ adrenoceptor antagonism of the present compounds. As evidence of central (X2-adrenoceptor blockade in vivo, the reversal of the loss of righting reflex observed in rats after intravenous injection of xylazine and inhibition of the tremors induced by reserpine in the rats is used.

The compounds of the present invention also have the ability to rapidly penetrate the central nervous system.

For purposes of administration, the present compounds may be formulated in various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salt or in free acid or base form, as the active ingredient is combined in dense admixture with a pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the desired preparation form for administration. These pharmaceutical compositions are desirably in unit dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, all the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. Injectable solutions can, for example, be prepared where the carrier comprises salt solution, glucose solution or a mixture of salt and glucose solution. Injectable solutions containing compounds of formula (I) can be formulated in an oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures of these and other oils. Injectable suspensions can also be prepared in which case suitable liquid carriers, suspending agents and the like can be used. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor portions, the additives causing no significant harmful effects on the skin. The additives may facilitate administration to the skin and/or may be of help in preparing the desired compositions. These compositions can be administered in various ways, eg, as a transdermal patch, as a "spot-on" or as an ointment. Addition salts of (I) are, due to their increased water solubility over the corresponding free base or free acid form, obviously more suitable in the preparation of aqueous compositions.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form to facilitate administration and uniformity of dosage. Dosage unit form as used in the description and claims hereinafter refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, biscuits, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

The following examples are intended to illustrate the present invention.

Experimental part

A. Preparation of the intermediates

Example Al

A mixture of O-phenylhydroxylamine hydrochloride (1:1)

(0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) were stirred at 20°C. HC1

(353 ml) was added dropwise at 20°C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out with stirring.

The precipitate was filtered off, washed with 2-propanol and diisopropyl ether, then dried to give 84 g (64%) of 1,2,3,4-tetrahydrobenzo-furo[3,2-c]pyridine hydrochloride (1:1) (interim 1).

Example A2

a) Reaction under N2 atmosphere. NaH 60% (0.17 mol) was stirred in tetrahydrofuran (350 mL). A solution of diethyl(cyanomethyl)phosphonate (0.17 mol) in tetrahydrofuran (150 ml) was added dropwise over ± 20 minutes, (exothermic temperature rise to 30°C). The mixture was stirred for 20 minutes at room temperature, then cooled to 0°C. A solution of 5-methyl-3(2H)-benzofuranone (0.15 mol) in tetrahydrofuran (350 mL) was added dropwise over 30 minutes at 0°C. The reaction mixture was stirred overnight at room temperature, then poured into water (1500 mL) and stirred. This mixture was extracted with ether, diisopropyl ether (2x), dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50). The desired fractions were collected and the solvent was evaporated, yielding 21.2 g (82%) of 5-methyl-3-benzofuranacetonitrile (interm. 2). b) A mixture of intermediate (2) (0.12 mol) in NH3/CH3OH (400 mL) was hydrogenated with Raney nickel (3 g) as a

catalyst. After uptake of H 2 (2 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2C12/-

(CH3OH/NH3) 98/2 to 96/4). The desired fractions were collected and the solvent was evaporated. The residue (± 2.1 g) was dissolved in 2-propanol (500 ml), and converted to the hydrochloric acid salt (1:1) with HC1/2-propanol. The mixture was stirred at room temperature. The solvent was evaporated. The residue was stirred in diisopropyl ether, filtered off and dried to give 24.4 g (96%) of 5-methyl-3-benzofuranethanamine hydrochloride (1:1) (interm. 3).

c) A mixture of intermediate (3) (0.0024 mol) in HzO (2 ml), acetic acid (2 ml) and formol 37% (2 ml) was stirred in a

hour at 100°C. The reaction mixture was cooled and poured into 1 M NaOH (50 mL). The precipitate was filtered off, washed with water, then dissolved in 1 N HCl (100 mL). The mixture was stirred for 15 minutes in a hot water bath (80°C). The solvent was evaporated. 2-Propanol was added. The solvent was evaporated. The residue was stirred in boiling 2-propanone, then allowed to cool to room temperature with stirring. The precipitate was filtered off and dried, yielding 0.40 g of 1,2,3,4-(tetrahydro-6-methylbenzofuro[2,3-c]pyridine monohydrochloride monohydrate (interm. 4).

Example A3

a) Butyllithium (0.27 mol of a 2.5 M solution) was added dropwise to 6-methoxy-benzo[b]thiophene [prepared analogously

with the procedure described in J. Med. Chem. 1989, 32(12), 2548-2554] (0.25 mol) in tetrahydrofuran (1000 ml), stirred at -30°C. The mixture was stirred for 10 minutes at -30°C. Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at -30°C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH 2 Cl 2 . The separated organic phase was dried, filtered and the solvent was evaporated. The residue was stirred in hexane, filtered off and dried to give 41.3 g of 6-methoxybenzo[b]thiophene-2-ethanol (interm. 5).

b) Methanesulfonyl chloride (0.21 mol) was added to a mixture of intermediate 5 (0.19 mol) and triethylamine (0.21

mol) in CH2Cl2 (1000 mL), stirred at 0°C. The reaction mixture was stirred for 4 hours at room temperature, then poured into water. The separated organic phase was dried, filtered and the solvent was evaporated. The residue was triturated under diisopropyl ether, filtered off and dried,

ket gave 50.5 g (94%) of 6-methoxybenzo[b]thiophene-2-ethanol methane sulfonate (ester) (interm. 6).

c) A mixture of intermediate 6 (0.18 mol) and Nal (0.45 mol) in 2-propanone (1000 mL) was stirred and refluxed for 9

hours, then cooled to room temperature and the solvent was evaporated. The residue was washed with water and extracted with CH 2 Cl 2 . The separated organic phase was dried, filtered and the solvent evaporated to give 57 g of 2-(2-iodoethyl)-6-methoxybenzo[b]thiophene (interm. 7).

d) Intermediate 7 (0.18 mol) was added portionwise to a mixture of 1,3,5,7-tetraazatricyclo[5,1,1,13,5]decane (0.45

mol) in CHCl 3 (600 mL). The reaction mixture was stirred and refluxed overnight, then cooled to room temperature. The precipitate was filtered off and dried, yielding 54.2 g of 1-[2-(6-methoxybenzo[b]thiophen-2-yl)ethyl]-1,3,5,7-tetraazatricyclo[5,1,1, 1 5,7]decanium iodide (interm. 8). e) A mixture of intermediate 8 (0.12 mol) and HCl (0.50 mol) in ethanol (171 mL) was stirred for 2 days at room temperature. More HCl (10 mL) and ethanol (40 mL) were added and the reaction mixture was stirred and refluxed for one hour, then cooled to room temperature. The solvent was evaporated. The residue was stirred in 2-propanol, then filtered off. The solid was dried and the residue was again converted to the four base with 20% NaOH. The separated organic phase was dried, filtered and the solvent was evaporated. The residue was dissolved in 2-propanol and converted to the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 13.1 g (50%) of 1,2,3,4-tetrahydro-7-methoxy-[1]benzothieno[3,2-c]pyridine {interm.

9) -

Analogously, 1,2,3,4-tetrahydro-8-methyl-[ljbenzothieno[3,2-c]pyridine hydrochloride (interm. 10) was prepared.

Example A4

a) A mixture of formol (37%; 31 g) and ZnCl2 (10 g) in ethyl acetate (90 mL) and HCl (12 N; 190 mL) was stirred at -

10°C. HCl (gas) was allowed to bubble through the mixture until saturation (at -10°C). 5-Fluoro-benzo[b]thiophene (0.35 mol) was added dropwise at <0°C. The reaction mixture was stirred overnight at room temperature. Toluene (200 mL) was added and the mixture was vigorously stirred. The organic phase was separated, washed with an aqueous NaHCC-3 solution and with water, dried, filtered and the solvent was evaporated. The residue was triturated under hexane, filtered off and dried to give 58 g (82.6%) of 3-(chloromethyl)-5-fluoro-benzo[b]-thiophene (interm 11). b) A mixture of NaCN (0.33 mol) and dibenzo-18-crown ether (0.050 g) in dimethyl sulfoxide (110 ml) was stirred at 30°C.

Intermediate 11 (0.29 mol) was added slowly. The mixture was allowed to cool to room temperature with stirring. The reaction mixture was then stirred in ice water. The precipitate was filtered off, washed with water, then dissolved in CH 2 Cl 2 . The organic solution was dried, filtered and the solvent evaporated to give 5-fluorobenzo-[b]thiophene-3-acetonitrile (interm 12).

c) A mixture of intermediate 12 (0.29 mol) in a mixture of NH3 and CH3OH (700 mL) was hydrogenated at 14°C with

Raney nickel (5 g) as a catalyst in the presence of a thiophene solution (10 ml). After uptake of H 2 (2 equiv.), the catalyst was filtered off over dicalite and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /(CH 3 OH/NH 3 ) 96/4). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in diisopropyl ether and converted to the hydrochloric acid salt (1:1) with HC1/2-propanol. The precipitate was filtered off, washed with diisopropyl ether, and dried, yielding 48.5 g of 5-fluorobenzo[b]thiophene-3-ethanamine hydrochloride (interm. 13).

d) A mixture of intermediate 13 (0.21 mol) in water (190 mL), acetic acid (190 mL) and formol (37%; 190 mL) was stirred

and refluxed for one hour. The mixture was allowed to cool to room temperature, then poured into NaOH (4 M; 1200 mL), with stirring. The precipitate was filtered off and triturated under CH 3 CN, filtered off, washed with diisopropyl ether and dried to give 21 g of 1,1'-methylenebis[6-fluoro-1,2,3,4-tetra-hydro-[l]benzothieno[ 2,3-c]pyridine (interm. 14).

e) A mixture of intermediate 14 (0.049 mol) in water (1700 mL) and HCl (12 N; 285 mL) was stirred and refluxed in a

hour. The precipitate was filtered off, washed with CH 3 CN and diisopropyl ether, and dried to give 17.7 g of 6-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine hydrochloride (interm . 15).

Example A5

A mixture of AlCl 3 (32 g) in methoxybenzene (250 ml) was stirred at 0°C. 5-Chloropentanoyl chloride (0.24 mol) was added dropwise at 0°C. The reaction mixture was stirred for 3 hours at 0 to 5°C and then allowed to rise to 15°C. The mixture was poured into ice water (400 g) and HCl 12N (100 mL), and extracted with CH 2 Cl 2 . The organic phase was separated, dried, filtered over dicalite and the solvent was evaporated. The residue was stirred in petroleum ether and diisopropyl ether, and the resulting oil was separated, yielding 50.4 g of 6-chloro-1-(4-methoxyphenyl)-1-hexanone (interm. 16).

Example A6

a) Reaction under N2 atmosphere. BF 3 in diethyl ether (215 mL) was cooled to 0°C. 3-Fluorophenol (0.25 mol) was added. 6-Chlorohexanoyl chloride (0.51 mol) was added and the resulting reaction mixture was stirred for 15 min at 0°C, then allowed to warm to room temperature. The reaction mixture was then stirred overnight at 130°C. The mixture was cooled to room temperature. Water was added while cooling. This mixture was extracted twice with diisopropyl ether. The separated organic phase was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50), then by HPLC (eluent: CH2Cl2/hexane 50/50). The fractions were combined and the solvent was evaporated to give 52.2 g of 6-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-hexanone (interm 17). b) A mixture of intermediate 17 (0.21 mol) and hydroxylamine hydrochloride (0.25 mol) in pyridine (100 mL) was stirred for 2 days at room temperature, then poured into 1 N HCl (4 50 mL). This mixture was stirred for 10 min, then extracted with ethyl acetate (2x). The separated organic phase was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 99/1). The desired fractions were collected and the solvent was evaporated, yielding 22 g of 6-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-hexanone, oxime (interm. 18).c) Intermediate 18 (0.017 mol) in tetrahydrofuran (50 mL) was heated to 60°C. A solution of 1,1'-carbonylbis-1#-imidazole (0.035 mol) in tetrahydrofuran (200 mL) was added dropwise and the resulting reaction mixture was stirred and refluxed for 2 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was washed with water, then acidified with HCl. This mixture was extracted with CH 2 Cl 2 . The separated organic phase was dried, filtered and the solvent was evaporated.

The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 100%). The desired fractions were pooled and the solvent was , giving 3-(5-chloropentyl)-6-fluoro-1,2-benzisoxazole (interm. 19).

B. Preparation of the compounds of formula (I)

Example Bl

A mixture of 6-chloro-1-(4-fluorophenyl)-1-hexanone (0.018 mol), intermediate 1 (0.015 mol), Na 2 CO 3 (4 g) and potassium iodide (catalytic amount) in methyl isobutyl ketone (200 mL) was stirred and refluxed overnight and then cooled to room temperature. The solvent was evaporated. The residue was washed with H 2 O and the mixture was extracted with CH 2 Cl 2 . The organic phase was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was converted to the (E)-2-butenedioic acid salt (1:1). The precipitate was filtered off and dried, yielding 5.1 g of 1-(4-fluorophenyl)-6-(1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-2-yl)-1-hexanone -(E)-2-butenedioate (1:1) (71%).

Tables 1, 2 and 3 list compounds of formula (I) which were prepared analogously to example B1.

C. Pharmacological examples

Example C, 1: In vitro binding affinity for α-β receptors

The interaction of the compounds of formula (I) with O12 receptors was assessed in in vitro radioligand binding experiments.

In general, a low concentration of a radioligand with a high binding affinity for a particular receptor is incubated with a sample of a tissue prepared enriched in a particular receptor or with a preparation of cells expressing cloned human receptors in a buffered medium. During the incubation, the radioligand binds to the receptor. When binding equilibrium is reached, the receptor-bound radioactivity is separated from the unbound radioactivity, and the receptor-bound activity is counted. The interaction of the test compounds with the receptor is assessed in competitive binding experiments. Different concentrations of the test compound are added to the incubation mixture containing receptor preparations and the radioligand. Binding of the radioligand will be inhibited by the test compound in proportion to its binding affinity and its concentration.

The radioligand used for CC2A~/ a2B- and o<t>2C-reseP^or binding is <3>H-rauwolscin and the receptor preparation used is Chinese Hamster Ovary (CHO) cells expressing cloned human «2^-, «2B - and ct2c receptors •

The IC 50 value (concentration at which 50% of the receptors are inhibited) for the compounds exemplified in the experimental part above for each of the three receptors ranges between 10~<6> M and 10"<10> M.

Example C. 2: Dissociation in receptor binding affinity for o t2a and dopamine D2

As already mentioned above, dopamine D2 antagonism can lead to an increased risk of EPS. Thus, the greater the dissociation between a2a and D2, the better. The columns headed "dissociation" show the IC50 value in molar (M) for the α2a receptor and the D2 receptor. By "Ratio" is meant the ratio D2/a2a and this is an indication of the dissociation between the two receptors.

D. Composition examples

"Active ingredient" (A.I.) as used throughout these examples refers to a compound of formula (I), a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

Example D, 1 : Capsules

20 g of A.I., 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate are vigorously stirred together. The resulting mixture is then filled into 1000 suitably hardened gelatin capsules, each containing 20 mg of A.I.

Example D, 2: Film-coated tablets

Frein's tilling „of__tablet core

A mixture of 100 g of A.I., 570 g of lactose and 200 g of starch is mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 200 ml of water. The moist powder mixture is sieved, dried and sieved again. 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are then added. The whole is mixed well and compressed into tablets, yielding 10,000 tablets, each containing 10 mg of the active ingredient.

Coating

A solution of 5 g of ethyl cellulose in 150 ml of dichloromethane is added to a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol. 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are then added. 10 g of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then 2.5 g of magnesium octadecanoate, 5 g of polyvinyl pyrrolidone and 30 ml of concentrated color suspension are added and the whole is homogenized. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

Claims (7)

1. Connection with the formula an N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: Alk is 1-5-pentanediyl; n is 1 or 2; p is 1 and q is 2; or p is 2 and q is 1; X is -O-, -S- or NH; every r! is independently hydrogen, halogen, C 1-6 alkyl, nitro, hydroxy or C 1-4 alkyloxy; D is a radical of formula wherein m is 1 or 2; each r<3> is independently hydrogen, C 1-4 alkyl, C 1-4 alkyloxy or halo. 2. A compound according to claim 1, wherein n is 1 and Ri is hydrogen, chlorine, fluorine, methyl, methoxy or nitro. 3. Compound according to claim 1 or 2 for use as a medicine. A. Use of a compound according to claim 1 or 2 in the preparation of a drug for the treatment of depression or Parkinson's disease. 5. Composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to claim 1 or 2. 6. Method for producing a composition according to claim 5 by combining a compound according to claim 1 or 2 as the active ingredient in dense mixture with a pharmaceutically acceptable carrier. 7. Method for producing a compound according to claim 1, characterized by) to W-alkylate an intermediate of formula (II) with a alkylating reagent of formula (III) wherein W<1> is a suitable leaving group and D, Alk, X, n and R<1> are as defined in claim 1, in a reaction-initiated solvent, in the presence of a base and optionally in the presence of a catalyst; b) and if desired, to convert compounds of formula (I) into each other by following transformations known in the art, and further, if desired, to convert the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or to a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, to convert the acid addition salt form to the free base by treatment with alkali, or to convert the base addition salt to the free acid by treatment with acid; and, if desired, prepare stereochemically isomeric forms or W-oxides thereof.